Pharmaceutical composition of protein kinase inhibitor

Abstract

A pharmaceutical composition of compound N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof, and a preparation method therefor and the use thereof.

Description

Pharmaceutical compositions of protein kinase inhibitors Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a pharmaceutical composition of a protein kinase inhibitor, its preparation method, and its uses. Background Technology

[0002] Mitogen-activated extracellular signal-regulated kinase (MEK) is an attractive therapeutic target because the only known substrates for MEK phosphorylation are MAP kinases ERK1 and ERK2. Constitutive activation of MEK / ERK has been found in primary tumor samples from the pancreas, colon, lung, kidney, and ovary.

[0003] Compound N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) is a MEK inhibitor, see WO2014 / 169843A1, and has the following structure:

[0004] No stable, bioavailable oral formulations of compound I for clinical use have been reported in the prior art.

[0005] Summary of the Invention

[0006] In a first aspect, the present invention provides a pharmaceutical composition comprising a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; b) at least one carrier; wherein compound I or a pharmaceutically acceptable salt thereof is distributed substantially in an amorphous form in the carrier.

[0007] In one embodiment, the total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition comprises no more than about 5% of compound I or a pharmaceutically acceptable salt thereof in crystalline form.

[0008] In one embodiment, the crystalline form of compound I has a characteristic diffraction peak at the following 2θ angle: 8.89 ± 0.2°.

[0009] In one embodiment, the pharmaceutical composition further comprises d) at least one pharmaceutically acceptable excipient.

[0010] In one embodiment, the pharmaceutical composition is an oral solid dosage form.

[0011] In a second aspect, the present invention provides a method for treating, improving, or preventing melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis, said method comprising administering to an individual in need an effective amount of the pharmaceutical composition as described in the first aspect of the present invention.

[0012] Thirdly, the present invention provides the use of the pharmaceutical composition as described in the first aspect of the present invention in the preparation of a medicament, the medicament being used to treat, improve or prevent melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis. Attached Figure Description

[0013] Figure 1: XRPD pattern of crystal form A of compound I.

[0014] Figure 2: DSC spectrum of crystal form A of compound I.

[0015] Figure 3: TGA spectrum of crystal form A of compound I.

[0016] Figure 4: XRPD pattern of crystal form B of compound I.

[0017] Figure 5: XRPD pattern of crystal form C of compound I.

[0018] Figure 6: 6A: XRPD pattern of compound I, crystal form D. 6B: XRPD pattern of compound I, crystal form D after heating to 200℃. 6C: XRPD pattern of compound I, crystal form A.

[0019] Figure 7: DSC spectrum of compound I crystal form D: The first endothermic peak has an onset temperature of 137.60℃, a peak temperature of 147.45℃, and a normalized enthalpy of 18.036 J / g; the second endothermic peak has an onset temperature of 152.73℃, a peak temperature of 155.36℃, and a normalized enthalpy of 42.887 J / g; the third endothermic peak has an onset temperature of 279.68℃, a peak temperature of 280.69℃, and a normalized enthalpy of 85.383 J / g. 7B: TGA spectrum of compound I, crystal form D: weight loss of 0.147 mg at 100-165℃, weight loss percentage of 5.398%; weight loss of 0.099 mg at 165-200℃, weight loss percentage of 3.636%; weight loss of 0.019 mg at 250-300℃, weight loss percentage of 0.681%.

[0020] Figure 8: Crystal form D of compound I 1 H-NMR spectrum.

[0021] Figure 9: Overlay of XRPD spectra of compound I crystal form A in a humidity-induced experiment.

[0022] Figure 10: XRPD plot of the influencing factors of crystal form A of compound I.

[0023] Figure 11: Accelerated XRPD spectrum of compound I crystal form A - 6 months - control.

[0024] Figure 12: Accelerated XRPD spectrum of compound I crystal form A - 6 months - test sample.

[0025] Figure 13: XRPD spectrum of compound I crystal form A over a long period of time - 24 months - control.

[0026] Figure 14: XRPD spectrum of compound I crystal form A over a long period of time - 24 months - test sample.

[0027] Figure 15: XRPD spectrum of solid dispersion of compound I. Detailed Implementation

[0028] The present invention will now be described in further detail. This description is for illustrative purposes only and is not intended to limit the invention. Those skilled in the art will readily understand other advantages and effects of the invention from the disclosure herein. The invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the invention.

[0029] General definitions and terms

[0030] Unless otherwise stated, all publications, patent applications, patents and other references mentioned herein are incorporated herein in their entirety by way of citation.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail.

[0032] Unless otherwise stated, all percentages, parts, proportions, etc., are by weight. Unless otherwise stated, concentrations are by weight, liquid proportions in mixed solutions are by volume, and the ratios (including percentages) of reagents to compounds and reaction yields are by moles.

[0033] When a quantity, concentration, or other value or parameter is given as a range, preferred range, or preferred upper and lower limits, or a specific value, it should be understood as specifically disclosing all ranges formed by pairs of values ​​from any upper or preferred range and any lower or preferred range, regardless of whether the range is disclosed individually. Unless otherwise stated, when a numerical range is referred to herein, the range means including its endpoints and all integers and fractions within that range. The scope of this invention is not limited to the specific numerical value referenced when defining the range. For example, "1-20" encompasses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and any subrange consisting of any two values ​​therein, such as 2-6, 3-5, 2-10, 3-15, 4-20, 5-19, etc. For example, "1:1-1:5" covers 1:1, 1:2, 1:3, 1:4, 1:5, and any subrange consisting of any two of these values, such as 1:1-1:4, 1:1-1:3, 1:1-1:2, 1:2-1:4, 1:2-1:3, etc.

[0034] The terms “about” and “approximately” as used in this article, when used with a numerical variable, generally mean that the value of the variable and all values ​​of the variable are within the experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or a wider range.

[0035] As used in this document, the term “selected from…” means one or more elements from the groups listed below, selected independently, and may include combinations of two or more elements.

[0036] As used herein, the terms “one or more” or “at least one” refer to one, two, three, four, five, six, seven, eight, nine or more.

[0037] Unless otherwise stated, the terms "combination thereof" and "mixture thereof" refer to a multi-component mixture of the elements, such as two, three, four, and up to the maximum possible multi-component mixture.

[0038] Furthermore, if the number of components or parts of the present invention is not previously specified, it indicates that there is no limitation on the number of occurrences (or presence) of the components or parts. Therefore, it should be interpreted as including one or at least one, and the singular form of a component or part also includes the plural, unless the value clearly indicates a singular number.

[0039] As used herein, the terms “optional” or “optionally” mean that an event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of the event or condition.

[0040] The terms “comprising,” “including,” “having,” “containing,” or “involving,” as used herein, and their other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the foregoing term “comprising” covers the meaning of “consisting of.” The expression “consisting of” excludes any unspecified element, step, or ingredient. The expression “substantially constitutes” limits the scope to the specified elements, steps, or ingredients, plus optional elements, steps, or ingredients that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expression “comprising” encompasses both the expressions “substantially constitutes” and “consisting of.”

[0041] The term "pharmaceutically acceptable" as used in this article means that, within the bounds of normal medical judgment, contact with a patient's tissues will not cause undue toxicity, irritation, allergic reactions, etc., and that the benefits and risks are reasonable and that the product is effective for its intended use.

[0042] As used in this article, the terms “crystal form” or “crystal” or “crystallization” refer to any solid substance exhibiting a three-dimensional arrangement, as opposed to amorphous substances, which produce characteristic X-ray powder diffraction patterns with well-defined beehives.

[0043] The term “amorphous” as used in this article refers to any solid material that is not ordered in three dimensions.

[0044] The term “substantially amorphous” as used in this article means that more than 95% of it exists in an amorphous form, or that no more than 5% of it exists in a crystalline form.

[0045] As used in this article, the term "anhydrous" means that the compounds provided herein do not contain stoichiometric or nonstoichiometric amounts of water bound together by noncovalent intermolecular forces.

[0046] The term “non-covalent bond” as used in this article refers to weak intermolecular interactions other than covalent bonds, including but not limited to hydrogen bonds, van der Waals forces, salt bonds, hydrophobic interactions, aromatic ring stacking, π-π stacking, halogen bonds, etc.

[0047] The term “X-ray powder diffraction pattern (XRPD pattern)” as used in this article refers to an experimentally observed diffraction pattern or parameters derived from it. XRPD patterns are typically characterized by peak position (x-axis) and / or peak intensity (y-axis).

[0048] In XRPD patterns, diffraction patterns obtained from crystalline compounds are often characteristic of a specific crystal form. The relative intensities of bands (especially at low angles) can vary due to dominant orientation effects resulting from differences in crystallization conditions, grain size, and other measurement conditions. Therefore, the relative intensities of diffraction peaks are not characteristic of the specific crystal form. When determining whether a crystal form is identical to a known crystal form, attention should be paid to the relative positions of the peaks rather than their relative intensities. Furthermore, slight errors in peak positions are possible for any given crystal form, which is well known in crystallography. For example, peak positions can shift due to variations in temperature during sample analysis, sample movement, or instrument calibration; the measurement error for 2θ values ​​can sometimes be approximately ±0.2°. Therefore, this error should be taken into account when determining the structure of each crystal form. If the crystal forms of the present invention are described substantially as shown in the specified figures, the term "substantially" is also intended to cover such differences in diffraction peak positions.

[0049] In XRPD spectra, peak positions are typically represented by the 2θ angle or the interplanar distance d, with a simple conversion: d = λ / 2sinθ, where d represents the interplanar distance, λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. For the same crystal form of the same compound, the peak positions in their XRPD spectra are generally similar, although the relative intensity error may be relatively large. It should also be noted that in the identification of mixtures, factors such as decreased content may cause the absence of some diffraction lines. In such cases, it is not necessary to rely on all bands observed in a high-purity sample; even a single band may be characteristic of a given crystal.

[0050] As used herein, the term "2θ" refers to the peak position in degrees, as defined in an experimental setup based on X-ray powder diffraction experiments, and is typically expressed in units of the horizontal axis in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that specific 2θ values ​​for particular crystal forms mentioned herein are intended to represent 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0051] The term "thermogravimetric analysis (TGA) spectrum" as used in this article refers to the curve recorded by a thermogravimetric analyzer. TGA is a common method for determining the thermal stability of compounds. In this article, TGA is also used to determine the hydration state of compounds. The heating rate during the test can have a certain impact on the spectrum. For example, excessively high heating rates are not conducive to the detection of intermediate products.

[0052] The term "differential scanning calorimetry (DSC) spectrum" as used in this article refers to a curve recorded by a differential scanning calorimeter. DSC determines the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point is typically within about 3 °C in consecutive analyses. When describing a compound as having a given DSC peak or melting point, it refers to that DSC peak or melting point ±3 °C. This temperature variation is also "substantially" taken into account. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0053] The term "nuclear magnetic resonance" as used in this article 1 "H-NMR spectrum" refers to the signal peaks recorded by a nuclear magnetic resonance spectrometer.

[0054] The term "particle size distribution (PSD)" as used in this article refers to the range of particle size distributions, which can be expressed as the particle size corresponding to a specific value when the cumulative particle size distribution ratio (e.g., expressed as a fraction, decimal, or percentage) reaches a certain value. For example, D(0.5) or D50 represents the median particle size. Particle size distribution can be measured by laser diffraction, for example, using the Mastersizer laser particle size analyzer from Malvern Instruments, Inc.

[0055] As used in this article, the term "active pharmaceutical ingredient (API)" refers to a chemical entity that can effectively treat or prevent a target disease or condition.

[0056] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical active ingredient, which is optionally combined with one or more pharmaceutically acceptable chemical components (e.g., but not limited to carriers and / or excipients).

[0057] As used herein, the term "solid dispersion" refers to a solid system comprising at least two components, one of which is more or less uniformly dispersed throughout the other one or more components. When the dispersion of the components results in a chemically and physically homogeneous or homogeneous system, or when it consists of a single phase as defined in thermodynamics, such a solid dispersion will be referred to herein as a "solid solution." Solid solutions are preferred physical systems because the components therein are generally readily bioavailable to the organism administering the components. This advantage can be explained by the fact that solid solutions readily form liquid solutions upon contact with liquid media such as gastric juice. The ease of dissolution can be attributed at least in part to the fact that the energy required to dissolve a component from a solid solution is less than the energy required to dissolve a component from a crystalline or microcrystalline solid phase.

[0058] As used herein, the term "solid dispersion" also includes dispersions with lower overall homogeneity than solid solutions. Such dispersions are chemically and physically homogeneous or contain more than one phase. For example, the term "solid dispersion" also refers to a solid system comprising at least two components (a) and (b) and having multiple domains or small regions, wherein (a) is amorphous, microcrystalline, or crystalline, or (b) is amorphous, microcrystalline, or crystalline, or both are more or less homogeneously dispersed in another phase comprising (b) or (a) or in a solid solution comprising (a) and (b). A domain is a region that has some significantly different physical characteristics compared to the overall size of the system, is small in size, and is uniformly and randomly distributed throughout the system.

[0059] As used herein, the term "pharmaceuticalally acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair the bioactivity and properties of the active pharmaceutical ingredient, including but not limited to any fillers, flow aids, lubricants, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are acceptable for use in humans or animals.

[0060] As used in this article, "bioequivalence" refers to the acceptable difference between the rate and extent of absorption of the test drug and the reference drug after single or multiple administrations of the same dose under similar experimental conditions. This difference is exemplified by key pharmacokinetic parameters (AUC and C2) of the test and reference formulations. max A 90% confidence interval for the geometric mean ratio falling within the range of 80.00%–125.00% is considered to be bioequivalent.

[0061] As used herein, the terms “administration” or “giving” refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), local, and rectal administration.

[0062] The term "treatment" and other grammatical equivalents as used herein include alleviating, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, such as preventing the development of a disease or symptom; alleviating a disease or symptom; promoting the resolution of a disease or symptom; alleviating symptoms caused by a disease or symptom; or stopping the symptoms of a disease or symptom; and is intended to include prevention. The term also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the underlying condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, such that improvement is observable in the patient even though the patient may still have the underlying condition. For preventive benefits, the composition may be administered to a patient at risk of developing a specific disease or a patient who has reported one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0063] In this document, with respect to pharmaceuticals or pharmacologically active agents, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of this invention, the "effective amount" of one active substance in the composition may be the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0064] The term “individual” as used in this article includes humans or non-human animals, especially humans.

[0065] Pharmaceutical Composition

[0066] One aspect of the present invention is to provide a pharmaceutical composition comprising: a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; and b) at least one carrier; wherein compound I or a pharmaceutically acceptable salt thereof is distributed substantially in an amorphous form in the carrier.

[0067] Suitable carriers for use in the pharmaceutical compositions of the present invention are hydrophilic or water-soluble substances at least within a certain pH range, particularly at pH values ​​present in the gastrointestinal tract, including but not limited to:

[0068] Homopolymers and copolymers of N-vinyl lactams, particularly homopolymers and copolymers of N-vinylpyrrolidone, such as homopolymer polyvinylpyrrolidone (PVP or polyvinylpyrrolidone), copolymers containing N-vinylpyrrolidone and vinyl acetate monomers (copolyvinylpyrrolidone), or copolymers containing N-vinylpyrrolidone and vinyl propionate monomers. Aqueous solutions of polyvinylpyrrolidone have a certain viscosity, expressed as a K value. Suitable polyvinylpyrrolidones include, but are not limited to, PVP K15, PVP K17, PVP K25, PVP K30, PVP K29 / 32, PVP K60, and PVP K90. Copolyvinylpyrrolidones have different grades and specifications due to different ratios of the two monomers and different polymerization conditions. Suitable copolyvinylpyrrolidones include, but are not limited to, copolymers prepared from approximately 60% N-vinylpyrrolidone and approximately 40% ethyl acetate monomers, such as PVP S630.

[0069] Polyalkylene glycols, especially polyethylene glycols, such as PEG3350, PEG4000, PEG6000, PEG8000, PEG20000 or combinations thereof;

[0070] Cellulose esters and cellulose ethers, such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose), ethyl cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCS), hydroxypropyl methylcellulose acetate succinate (HPMCAS); suitable cellulose esters and cellulose ethers include, but are not limited to, HPMC E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC AS-LF, HPMC AS-MF, HPMC AS-HF, HPMC AS-LG, HPMC AS-MG, HPMC AS-HG, HPMCP-HP50, HPMCP-HP55, or combinations thereof;

[0071] High molecular weight polyepoxides, such as polyethylene oxides (PEGs or PEOs) and copolymers of ethylene oxide and propylene oxide (poloxam); suitable poloxamers include, but are not limited to, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 or combinations thereof.

[0072] Polyacrylates and polymethacrylates, such as methacrylate / ethyl acrylate copolymers, methacrylate / methyl methacrylate copolymers, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylate) and poly(hydroxyalkyl methacrylate);

[0073] Polyacrylamide;

[0074] Vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid, polyvinyl acetate, polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate (also known as partially saponified polyvinyl alcohol);

[0075] Graft copolymers of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate, such as BASF's Soluplus. TM Or equivalent products;

[0076] Oligosaccharides and polysaccharides, such as carrageenan, chitosan, chitosan polysaccharide, galactomannan and xanthan gum;

[0077] and mixtures of two or more of them.

[0078] Preferably, the carrier in the pharmaceutical composition of the present invention is selected from one or a combination of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate, more preferably copovidone, polyvinylpyrrolidone, or a combination thereof, and most preferably polyvinylpyrrolidone.

[0079] In the pharmaceutical compositions of the present invention, the weight ratio of compound I or a pharmaceutically acceptable salt thereof to the carrier is in the range of about 1:1 to about 1:10, for example, it can be about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. Preferably, the weight ratio of compound I or a pharmaceutically acceptable salt thereof to the carrier in the pharmaceutical compositions of the present invention is in the range of about 1:3 to about 1:7, more preferably in the range of about 1:4 to about 1:6.

[0080] This invention, through in-depth research on the type of carrier and the ratio of carrier to active pharmaceutical ingredient, enables compound I or its pharmaceutically acceptable salt to be distributed in the carrier in a substantially amorphous form, significantly improving the dissolution of compound I or its pharmaceutically acceptable salt. At the same time, it ensures the stability of the pharmaceutical composition. Even after long-term storage, compound I or its pharmaceutically acceptable salt remains in an amorphous form without crystal precipitation, thus avoiding dissolution limitations caused by the low solubility of crystalline forms.

[0081] In one embodiment, the pharmaceutical composition of the present invention further comprises: c) at least one surfactant.

[0082] Surfactants suitable for use in the pharmaceutical compositions of the present invention are substances capable of improving the dissolution of the active pharmaceutical ingredient, and may be anionic surfactants, nonionic surfactants, or combinations thereof, including but not limited to:

[0083] Carboxylates, such as potassium oleate, sodium oleate, aluminum monostearate, and calcium monostearate;

[0084] Sulfate salts, such as sodium hexadecyl sulfate (sodium myristyl sulfate), sodium tetradecyl sulfate, monoethanolamine dodecyl sulfate (monoethanolamine lauryl sulfate), sodium dodecyl sulfate (sodium lauryl sulfate; SLS; SDS), and sodium cetearyl sulfate;

[0085] Sulfonates, such as sodium dodecylbenzenesulfonate;

[0086] Phosphate salts, such as ethylene glycol phosphate;

[0087] Polyoxyethylene castor oil derivatives, such as PEG-35 castor oil (e.g., BASF's Cremophor EL). TM (or equivalent products), PEG-40 hydrogenated castor oil (e.g., Cremophor RH) TM 40 or equivalent products) and PEG-60 hydrogenated castor oil (e.g., Cremophor RH) TM 60 or equivalent products);

[0088] Other polyoxyethylene glycerides, such as PEG-32 glyceryl laurate (e.g., Gattefossé's Gelucire) TM 44 / 14 or equivalent products) and PEG-32 glyceryl palmitate (e.g., Gelucire) TM 50 / 13 or equivalent products) and Labrafil M1944CS (oleoyl polyethylene glycol 6 glyceryl ester prepared by transesterification of almond oil with PEG300);

[0089] Fatty acid monoesters of sorbitol, such as sorbitol monooleate (e.g., Span TM 80 or equivalent products), sorbitan monostearate (e.g., Span TM 60 or equivalent products), dehydrated sorbitan monopalmitate (e.g., Span TM 40 or equivalent products) and dehydrated sorbitol monolaurate (e.g., Span TM 20 or equivalent products);

[0090] Other fatty acid esters of sorbitol, such as sorbitol tristearate and sorbitol trioleate;

[0091] Polyoxyethylene sorbitol fatty acid monoesters (polysorbates), such as PEG-20 sorbitol monooleate (polysorbate 80, e.g., Tween). TM 80 or equivalent products), PEG-20 dehydrated sorbitan monostearate (polysorbate 60, e.g., Tween) TM 60 or equivalent products), PEG-20 dehydrated sorbitan monopalmitate (polysorbate 40, e.g., Tween TM 40 or equivalent products) or PEG-20 dehydrated sorbitol monolaurate (polysorbate 20, e.g., Tween) TM 20 or equivalent products);

[0092] Other fatty acid esters of polyoxyethylene sorbitol, such as PEG(20) sorbitol tristearate (Tween65) and PEG(20) sorbitol trioleate (Tween85);

[0093] Fatty acid esters of polyalkylene glycols, such as PEG660 hydroxy-stearic acid (12-hydroxystearic acid (70 mol%)) and polyethylene glycol (30 mol%).

[0094] Polyalkoxylated ethers of fatty alcohols, such as PEG(2) stearate (Brij72), polyethylene glycol 6 cetearate or polyethylene glycol 25 cetearate;

[0095] Tocopherol compounds, such as α-tocopherol polyethylene glycol succinate (vitamin E-TPGS);

[0096] and mixtures of two or more of them.

[0097] Preferably, the surfactant in the pharmaceutical composition of the present invention is selected from one or a combination of sodium dodecyl sulfate, polysorbate 80, and vitamin E-TPGS, more preferably sodium dodecyl sulfate, polysorbate 80, or a combination thereof, and most preferably sodium dodecyl sulfate.

[0098] In the pharmaceutical compositions of the present invention, the weight ratio of compound I or a pharmaceutically acceptable salt thereof to surfactant is in the range of about 1:0.5 to about 1:2, for example, it can be about 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2. Preferably, the weight ratio of compound I or a pharmaceutically acceptable salt thereof to surfactant in the pharmaceutical compositions of the present invention is in the range of about 1:0.7 to about 1:1.3, more preferably in the range of about 1:0.9 to about 1:1.1.

[0099] In the pharmaceutical compositions of the present invention, the weight ratio of compound I or its pharmaceutically acceptable salt:carrier:surfactant is in the range of about 1:1:0.5 to about 1:10:2, preferably in the range of about 1:3:0.7 to about 1:7:1.3, and more preferably in the range of about 1:4:0.9 to about 1:6:1.1.

[0100] This invention, through in-depth research on the types of surfactants, the ratio of surfactants to active pharmaceutical ingredients, and the carrier ratio, further improves the dissolution of compound I or its pharmaceutically acceptable salts, which helps to achieve the expected clinical application effects with lower dosages.

[0101] A pharmaceutically acceptable salt of compound I refers to a salt of compound I with a pharmaceutically acceptable non-toxic base or acid, including salts made from inorganic or organic bases and inorganic or organic acids. Pharmaceutically acceptable inorganic base salts may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Pharmaceutically acceptable organic base salts may be selected from primary, secondary, and tertiary amine salts. Substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. Pharmaceutically acceptable inorganic and organic acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.

[0102] In the pharmaceutical composition of the present invention, the total weight of compound I or a pharmaceutically acceptable salt thereof, wherein the crystalline form of compound I or a pharmaceutically acceptable salt thereof is present in no more than about 5%, preferably no more than about 4%, and more preferably no more than about 3%.

[0103] The crystalline form of compound I of this invention includes, but is not limited to, crystal form A, crystal form B, crystal form C, crystal form D, or mixtures thereof.

[0104] The X-ray powder diffraction pattern of compound I, crystal form A of the present invention, has a characteristic diffraction peak at the following 2θ angle: 8.89±0.2°.

[0105] In one embodiment, the X-ray powder diffraction pattern of crystal form A of compound I of the present invention has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, and 24.86±0.2°.

[0106] In one embodiment, the X-ray powder diffraction pattern of crystal form A of compound I of the present invention has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 21.22±0.2°, 21.79±0.2°, 22.54±0.2°, 24.25±0.2°, and 24.86±0.2°.

[0107] In one embodiment, the X-ray powder diffraction pattern of crystal form A of compound I of the present invention has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 18.62±0.2°, 21.22±0.2°, 21.79±0.2°, 22.54±0.2°, 23.06±0.2°, 23.48±0.2°, 24.25±0.2°, 24.86±0.2°, 26.13±0.2°, and 28.21±0.2°.

[0108] In one embodiment, the X-ray powder diffraction pattern of crystal form A of compound I of the present invention is essentially as shown in Figure 1.

[0109] In one embodiment, the X-ray powder diffraction pattern of crystal form A of compound I of the present invention has a characteristic diffraction peak at the 2θ angle as shown in Table 1.

[0110] Table 1. XRPD pattern analysis data for crystal form A

[0111] In one embodiment, the differential scanning calorimetry spectrum of crystal form A of compound I of the present invention has an endothermic peak at 280.12±3℃.

[0112] In one embodiment, the differential scanning calorimeter of crystal form A of compound I of the present invention is essentially as shown in Figure 2.

[0113] In one embodiment, the thermogravimetric analysis (TGA) spectrum of compound I, crystal form A of the present invention, shows a weight loss of 0.07% at 105.00 ± 3 °C.

[0114] In one embodiment, the thermogravimetric analysis spectrum of the compound I crystal form A of the present invention is essentially as shown in Figure 3.

[0115] In one embodiment, the crystal form A of compound I of the present invention is anhydrous.

[0116] In one embodiment, the crystal form A of compound I of the present invention is non-solventized.

[0117] The X-ray powder diffraction pattern of compound I, crystal form B, of this invention is basically as shown in Figure 4.

[0118] The X-ray powder diffraction pattern of compound I, crystal form C, of ​​this invention is basically as shown in Figure 5.

[0119] The X-ray powder diffraction pattern of compound I, crystal form D of the present invention is basically as shown in Figure 6A.

[0120] The differential scanning calorimetry spectrum of compound I, crystal form D of the present invention, shows an endothermic peak at 137.60±3℃ and 152.73±3℃, respectively.

[0121] In one embodiment, the differential scanning calorimeter of crystal form D of compound I of the present invention is substantially as shown in 7A of FIG7.

[0122] In one embodiment, the thermogravimetric analysis (TGA) spectrum of the compound I crystal form D of the present invention shows a weight loss of 5.40% at 100-165±3℃, a weight loss of 3.64% at 165-200±3℃, and a weight loss of 0.68% at 250-300±3℃.

[0123] In one embodiment, the thermogravimetric analysis spectrum of the compound I crystal form D of the present invention is essentially as shown in 7B of Figure 7.

[0124] In one embodiment, the crystal form D of compound I of the present invention is a dimethylformamide solvate of compound I.

[0125] In a preferred embodiment, the pharmaceutical composition of the present invention comprises: a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; and b) at least one carrier; wherein compound I or a pharmaceutically acceptable salt thereof is distributed substantially in an amorphous form in the carrier; wherein the carrier is selected from one or a combination of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, or other substances that are hydrophilic or water-soluble at pH present in the gastrointestinal tract.

[0126] Furthermore, the weight ratio of compound I or a pharmaceutically acceptable salt thereof to the carrier in the pharmaceutical composition is in the range of about 1:1 to 1:10, preferably in the range of about 1:3 to about 1:7; more preferably in the range of about 1:4 to about 1:6.

[0127] Furthermore, based on the total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, the crystalline form of compound I or a pharmaceutically acceptable salt thereof present does not exceed about 5%, preferably not more than about 4%, and more preferably not more than about 3%.

[0128] Furthermore, compound I in its crystalline form exhibits a characteristic diffraction peak at the following 2θ angle: 8.89±0.2°, preferably at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, 24.86±0.2°, or 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 21.22±0.2°, 21.79±0.2°, 22.5°. 4±0.2°, 24.25±0.2°, 24.86±0.2°, or 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 18.62±0.2°, 21.22±0.2°, 21.79±0.2°, 22.54±0.2°, 23.06±0.2°, 23.48±0.2°, 24.25±0.2°, 24.86±0.2°, 26.13±0.2°, 28.21±0.2°.

[0129] In a preferred embodiment, the pharmaceutical composition of the present invention comprises a) compound I or a pharmaceutically acceptable salt thereof; b) at least one carrier; and c) at least one surfactant; wherein said compound I or a pharmaceutically acceptable salt thereof is distributed substantially in an amorphous form in the carrier; wherein said carrier is selected from one or a combination of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, or other substances that are hydrophilic or water-soluble at pH present in the gastrointestinal tract; wherein said surfactant is selected from one or a combination of sodium dodecyl sulfate, polysorbate 80, vitamin E-TPGS, or other substances capable of improving the dissolution of compound I or a pharmaceutically acceptable salt thereof.

[0130] Furthermore, the weight ratio of compound I or its pharmaceutically acceptable salt to carrier to surfactant in the pharmaceutical composition is in the range of about 1:1:0.5 to about 1:10:2, preferably in the range of about 1:3:0.7 to about 1:7:1.3; more preferably in the range of about 1:4:0.9 to about 1:6:1.1.

[0131] Furthermore, based on the total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, the crystalline form of compound I or a pharmaceutically acceptable salt thereof present does not exceed about 5%, preferably not more than about 4%, and more preferably not more than about 3%.

[0132] Furthermore, compound I in its crystalline form exhibits a characteristic diffraction peak at the following 2θ angle: 8.89±0.2°, preferably at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, 24.86±0.2°, or 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 21.22±0.2°, 21.79±0.2°, 22.5°. 4±0.2°, 24.25±0.2°, 24.86±0.2°, or 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 18.62±0.2°, 21.22±0.2°, 21.79±0.2°, 22.54±0.2°, 23.06±0.2°, 23.48±0.2°, 24.25±0.2°, 24.86±0.2°, 26.13±0.2°, 28.21±0.2°.

[0133] In one embodiment, the pharmaceutical composition of the present invention is a solid dispersion.

[0134] Other optional components may be added to the solid dispersion of the present invention as needed, including but not limited to: one or more lubricants, flow aids, fillers, disintegrants, solubilizers, plasticizers and / or stabilizers. Examples of stabilizers include, but are not limited to, antioxidants, light stabilizers, free radical scavengers and antimicrobial agents.

[0135] The solid dispersion of the present invention can be prepared by methods such as hot melt extrusion, spray drying, and melt-solvent method.

[0136] The hot melt extrusion method for preparing the solid dispersion of the present invention comprises the following steps: 1) mixing compound I or a pharmaceutically acceptable salt thereof, a carrier and optionally a surfactant; 2) heating the blend obtained in step 1) until a homogeneous melt is obtained; 3) passing the melt obtained in step 3) through a nozzle; 4) cooling the melt until solidification.

[0137] The spray drying method for preparing the solid dispersion of the present invention comprises the following steps: 1) dissolving compound I or a pharmaceutically acceptable salt thereof, a carrier and optionally a surfactant in a solvent; 2) spray drying the solution obtained in step 1).

[0138] The melt-solvent method for preparing the solid dispersion of the present invention comprises the following steps: 1) dissolving compound I or a pharmaceutically acceptable salt thereof, optionally a surfactant, in a solvent; 2) heating the carrier to melt; 3) mixing the solution obtained in step 1) with the melt obtained in step 2); 4) evaporating to remove the solvent; 5) cooling until solidification.

[0139] Suitable solvents for spray drying or melt-solvent drying are any organic solvents that enable easy mixing of the compound I of the present invention or its pharmaceutically acceptable salt, carrier and optional surfactant therein, including but not limited to one or a combination of alcohols, ketones, esters, hydrocarbons, ethers, disubstituted amides.

[0140] The alcohol solvents include, but are not limited to, one or a combination of methanol, ethanol, n-propanol, isopropanol, and butanol; the ketone solvents include, but are not limited to, one or a combination of acetone, methyl ethyl ketone, and methyl isobutyl ketone; the lipid solvents include, but are not limited to, one or a combination of ethyl acetate, propyl acetate, and butyl acetate; the hydrocarbon solvents include, but are not limited to, one or a combination of dichloromethane, 1,1,1-trichloroethane, toluene, and xylene; the ether solvents include, but are not limited to, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, or a combination thereof; and the disubstituted amide solvents include, but are not limited to, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N-methylpyrrolidone, or a combination thereof.

[0141] In one embodiment, the solid dispersion of the present invention is prepared by spray drying, comprising the following steps: 1) dissolving compound I or a pharmaceutically acceptable salt thereof, a carrier and optionally a surfactant in a solvent; 2) spray drying the solution obtained in step 1); wherein the solvent is selected from one or a combination of ethanol, methanol, acetone, ethyl acetate, dichloromethane, tetrahydrofuran.

[0142] In a preferred embodiment, the solvent is selected from one or a combination of ethanol, methanol, acetone, and dichloromethane; more preferably, the solvent is selected from a mixture of acetone and ethanol (preferably anhydrous ethanol), a mixture of acetone and methanol, or a mixture of dichloromethane and methanol. In the mixture of acetone and ethanol (preferably anhydrous ethanol), the volume ratio of acetone to ethanol (preferably anhydrous ethanol) is approximately 0.5:1 to 1:2, preferably about 1:1; in the mixture of acetone and methanol, the volume ratio of acetone to methanol is approximately 5:1 to 3:1, preferably about 4:1; in the mixture of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is approximately 3:1 to 1:1, preferably about 2:1.

[0143] In a preferred embodiment, the spray drying method further includes step 3) vacuum drying.

[0144] The median particle size D (0.5) of the solid dispersion prepared by the spray drying method of the present invention is between 1 and 10 μm, preferably between 3 and 9 μm, and more preferably between 4 and 7 μm.

[0145] In one embodiment, the pharmaceutical composition of the present invention further comprises: d) at least one pharmaceutically acceptable excipient.

[0146] Preferably, the pharmaceutical composition of the present invention is a solid dosage form suitable for oral administration, including but not limited to tablets, capsules, granules or other oral solid dosage forms that can meet bioequivalence requirements.

[0147] In the pharmaceutical composition of the present invention, the content of compound I or a pharmaceutically acceptable salt thereof may be in the range of about 0.05% to about 3% (w / w), preferably in the range of about 0.05% to about 0.07% or in the range of about 0.1% to about 1.5% (w / w), more preferably in the range of about 0.3% to about 1.0% (w / w).

[0148] The pharmaceutical composition of the present invention contains 0.1 mg to 15 mg of compound I, for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg, preferably 0.1 mg, 0.5 mg, 1 mg, 4 mg, or 8 mg, and more preferably 1 mg or 4 mg.

[0149] Pharmaceutically acceptable excipients suitable for use in the pharmaceutical compositions of the present invention include, but are not limited to, fillers, flow aids, lubricants, and disintegrants.

[0150] The filler may be selected from one or a combination of lactose, sucrose, glucose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, tricalcium phosphate, calcium hydrogen phosphate, calcium carbonate, and calcium sulfate dihydrate, preferably one or a combination of lactose (e.g., anhydrous lactose), sucrose, glucose, mannitol, and sorbitol, more preferably one or a combination of lactose (e.g., anhydrous lactose), mannitol, and sorbitol. The content of the filler in the pharmaceutical composition of the present invention may be in the range of about 50% to about 90% (w / w), preferably in the range of about 70% to about 90% (w / w), more preferably in the range of about 80% to about 90% (w / w).

[0151] The flow aid may be selected from talc, colloidal silica, or a combination thereof, preferably colloidal silica. The content of the flow aid in the pharmaceutical composition of the present invention may be in the range of about 0.5% to about 10% (w / w), preferably in the range of about 1% to about 5%, and more preferably in the range of about 2% to about 3%.

[0152] The lubricant may be selected from one or a combination of magnesium stearate, calcium stearate, sodium stearate, sodium stearate fumarate, polyethylene glycol, and glyceryl behenate, preferably one or a combination of magnesium stearate, calcium stearate, sodium stearate, and sodium stearate fumarate, and more preferably magnesium stearate. The content of the lubricant in the pharmaceutical composition of the present invention may be in the range of about 0.2% to about 5.0% (w / w), preferably in the range of about 0.5% to about 2.5%, and more preferably in the range of about 1% to about 2% (w / w).

[0153] The disintegrant may be selected from one or a combination of pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, preferably one or a combination of sodium carboxymethyl starch, croscarmellose sodium, and calcium carboxymethyl cellulose. The content of the disintegrant in the pharmaceutical composition may be in the range of about 1% to about 15% (w / w), preferably in the range of about 4% to about 12% (w / w), and more preferably in the range of about 6% to about 10% (w / w).

[0154] Through in-depth research on the types and amounts of excipients in pharmaceutical compositions, this invention has obtained solid dosage forms suitable for oral administration. These formulations are stable, have good bioavailability, do not have a food effect, and can produce the expected clinical efficacy with relatively low doses.

[0155] Coloring agents, flavoring agents, seasoning agents, antioxidants, etc., may also be added to the pharmaceutical composition of the present invention as needed.

[0156] When the pharmaceutical composition of the present invention is a tablet, the tablet may, as desired, include a coating. The coating is a film coating, and the film coating material includes, but is not limited to, water-soluble film coatings and water-insoluble film coatings, preferably water-soluble coating materials, particularly gastrointestinal film coatings, such as film coating premixes containing hydroxypropyl methylcellulose, like those sold under the trade name Obadai. In the coated tablet, the weight gain of the coating relative to the tablet core can be in the range of about 1% to about 10% (w / w), preferably in the range of about 1% to about 8% (w / w), more preferably in the range of about 1% to about 5% (w / w).

[0157] In a preferred embodiment, the pharmaceutical composition of the present invention comprises a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; b) at least one carrier; c) at least one surfactant; and d) at least one pharmaceutically acceptable excipient; wherein said compound I or a pharmaceutically acceptable salt thereof is distributed substantially amorphously in the carrier; and said pharmaceutical composition is an oral solid dosage form.

[0158] Furthermore, the carrier is selected from one or a combination of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, or other hydrophilic or water-soluble substances present in the gastrointestinal tract at a given pH.

[0159] Furthermore, the at least one surfactant is selected from sodium dodecyl sulfate, polysorbate 80, vitamin E-TPGS, or a combination thereof, or other substances capable of improving the dissolution of compound I or its pharmaceutically acceptable salt.

[0160] Furthermore, the weight ratio of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition to at least one carrier to at least one surfactant is in the range of about 1:1:0.5 to about 1:10:2, preferably in the range of about 1:3:0.7 to about 1:7:1.3, and more preferably in the range of about 1:4:0.9 to about 1:6:1.1.

[0161] Furthermore, the content of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of about 0.05% to about 3% (w / w), preferably in the range of about 0.05% to about 0.07% or in the range of about 0.1% to about 1.5% (w / w), more preferably in the range of about 0.3% to about 1.0% (w / w); at least one pharmaceutically acceptable excipient in the pharmaceutical composition includes a filler, a flow aid, a lubricant, or a disintegrant; the content of the filler in the pharmaceutical composition is in the range of about 50% to about 90% (w / w), preferably in the range of about 70% to about 90% (w / w). More preferably, the content is in the range of about 80% to about 90% (w / w); the content of the gliding agent is in the range of about 0.5% to about 10% (w / w), preferably in the range of about 1% to about 5%, more preferably in the range of about 2% to about 3%; the content of the lubricant is in the range of about 0.2% to about 5.0% (w / w), preferably in the range of about 0.5% to about 2.5%, more preferably in the range of about 1% to about 2% (w / w); the content of the disintegrant is in the range of about 1% to about 15% (w / w), preferably in the range of about 4% to about 12% (w / w), more preferably in the range of about 6% to about 10% (w / w).

[0162] Furthermore, the filler is selected from one or a combination of lactose, mannitol, and sorbitol; the flow aid is selected from one or a combination of talc and colloidal silica; the lubricant is selected from one or a combination of magnesium stearate, calcium stearate, sodium stearate, and sodium stearate fumarate; and the disintegrant is selected from one or a combination of sodium carboxymethyl starch, croscarmellose sodium, and calcium carboxymethyl cellulose.

[0163] Furthermore, the pharmaceutical composition comprises a solid dispersion, wherein the compound I or a pharmaceutically acceptable salt thereof is distributed substantially in an amorphous form in a carrier.

[0164] Furthermore, based on the total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, the crystalline form of compound I or a pharmaceutically acceptable salt thereof present does not exceed 5%, preferably not more than 4%, and more preferably not more than 3%.

[0165] Furthermore, the crystalline form of compound I exhibits characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, preferably at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, 24.86±0.2°, or 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 21.22±0.2°, 21.79±0.2°, 22.54°. ±0.2°, 24.25±0.2°, 24.86±0.2°, or 8.89±0.2°, 14.00±0.2°, 16.50±0.2°, 16.81±0.2°, 18.25±0.2°, 18.62±0.2°, 21.22±0.2°, 21.79±0.2°, 22.54±0.2°, 23.06±0.2°, 23.48±0.2°, 24.25±0.2°, 24.86±0.2°, 26.13±0.2°, 28.21±0.2°.

[0166] In a preferred embodiment, the pharmaceutical composition of the present invention comprises: a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; b) at least one carrier; c) at least one surfactant; and d) at least one pharmaceutically acceptable excipient; wherein compound I or a pharmaceutically acceptable salt thereof is substantially amorphous. The compound I is distributed in a carrier in the form of a crystalline form; the total weight of the compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is such that the presence of crystalline compound I or a pharmaceutically acceptable salt thereof does not exceed 3%; the crystalline compound I has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, 24.86±0.2°; the weight ratio of compound I or a pharmaceutically acceptable salt thereof to carrier to surfactant is in the range of about 1:4:0.9 to about 1:6:1.1; wherein the carrier is selected from polyvinylpyrrolidone; wherein the surfactant is selected from sodium dodecyl sulfate; the content of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of about 0.05% to about 0.07% or in the range of about 0.3% to about 1.0% (w / w); the pharmaceutical composition is an oral solid dosage form.

[0167] In a preferred embodiment, the pharmaceutical composition of the present invention comprises: a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; b) at least one carrier; c) at least one surfactant; and d) at least one pharmaceutically acceptable excipient; wherein said compound I or a pharmaceutically acceptable salt thereof is distributed substantially amorphously in the carrier; and based on the total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, the crystalline form of compound I or a pharmaceutically acceptable salt thereof present therein is […]. The pharmaceutical composition contains no more than 3% pharmaceutically acceptable salts; wherein the crystalline form of compound I has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, 24.86±0.2°; wherein the weight ratio of compound I or a pharmaceutically acceptable salt to carrier to surfactant is 1:5:1; wherein the carrier is selected from polyvinylpyrrolidone; wherein the surfactant is selected from sodium dodecyl sulfate; the content of compound I or a pharmaceutically acceptable salt in the pharmaceutical composition is in the range of about 0.05% to about 0.07% or in the range of about 0.3% to about 1.0% (w / w); the pharmaceutical composition is an oral solid dosage form.

[0168] In a preferred embodiment, the pharmaceutical composition of the present invention comprises: a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; b) at least one carrier; c) at least one surfactant; and d) at least one pharmaceutically acceptable excipient; wherein said compound I or a pharmaceutically acceptable salt thereof is distributed substantially amorphously in the carrier; wherein, based on the total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, the presence of crystalline form of compound I or a pharmaceutically acceptable salt thereof does not exceed 3%; wherein the crystalline form of compound I has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.2°. 5±0.2°, 24.25±0.2°, 24.86±0.2°; wherein the weight ratio of compound I or a pharmaceutically acceptable salt thereof to carrier to surfactant is 1:5:1; wherein the carrier is selected from polyvinylpyrrolidone; wherein the surfactant is selected from sodium dodecyl sulfate; the content of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of about 0.05% to about 0.07% or in the range of about 0.3% to about 1.0% (w / w); the pharmaceutical composition is a tablet; the excipients include fillers, flow aids, lubricants, and disintegrants; the content of fillers in the pharmaceutical composition is in the range of about 80% to about 90% (w / w), the content of flow aids is in the range of about 2% to about 3% (w / w), the content of lubricants is in the range of about 1% to about 2% (w / w), and the content of disintegrants is in the range of about 6% to about 10% (w / w).

[0169] In a preferred embodiment, the pharmaceutical composition of the present invention comprises: a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; b) at least one carrier; c) at least one surfactant; and d) at least one pharmaceutically acceptable excipient; wherein said compound I or a pharmaceutically acceptable salt thereof is distributed substantially amorphously in the carrier; wherein, based on the total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, the presence of crystalline form of compound I or a pharmaceutically acceptable salt thereof does not exceed 3%; wherein the crystalline form of compound I has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, 24.86±0.2°; wherein the weight ratio of compound I or a pharmaceutically acceptable salt thereof to carrier to surfactant is 1:5:1; wherein the carrier is selected from polyvinylpyrrolidone; wherein the surfactant is selected from sodium dodecyl sulfate; wherein the content of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of about 0.05% to about 0.07% or in the range of about 0.3% to about 1.0% (w / w); the pharmaceutical composition is a tablet; the excipients include mannitol as a filler, magnesium stearate as a lubricant, colloidal silica as a flow aid, and croscarmellose sodium as a disintegrant; the pharmaceutical composition contains about 80% to about 90% (w / w) of mannitol as a filler, about 2% to about 3% of colloidal silica as a flow aid, about 1% to about 2% (w / w) of magnesium stearate as a lubricant, and about 6% to about 10% (w / w) of croscarmellose sodium as a disintegrant.

[0170] One aspect of the present invention is to provide a pillbox comprising the pharmaceutical composition described above and instructions for use including information on one or more ingredients, including an introduction to disease states suitable for taking the pharmaceutical composition, storage information of the pharmaceutical composition, dosing information, and instructions on how to use the pharmaceutical composition. In a particular embodiment, the pillbox comprises multiple dosage forms of compound I or a pharmaceutically acceptable salt thereof.

[0171] One aspect of the present invention is to provide an article comprising the pharmaceutical composition described above and packaging material. In one embodiment, the packaging material comprises a container holding the pharmaceutical composition. In a preferred embodiment, the container includes a label containing information including a description of the disease state suitable for taking the pharmaceutical composition, storage information, dosing information, and instructions on how to use the pharmaceutical composition. In a preferred embodiment, the article comprises multiple dosage forms of compound I or a pharmaceutically acceptable salt thereof.

[0172] The tablets of the present invention can be prepared by granulation and tableting or by direct tableting, with direct tableting being preferred, such as direct tableting of powder.

[0173] The direct compression method for preparing the tablets of the present invention comprises the following steps: 1) preparing a solid dispersion; 2) mixing the solid dispersion with at least one pharmaceutically acceptable excipient; 3) compressing; and 4) optionally coating.

[0174] In a preferred embodiment, the solid dispersion is prepared by spray drying as defined above.

[0175] In a preferred embodiment, in step 2), a portion of the filler is premixed, then the solid dispersion, disintegrant, gliding agent, and the remaining filler are added and mixed, and finally the lubricant is added and mixed. Preferably, the portion of the filler refers to a filler accounting for approximately 1 / 3 to 3 / 5 of the prescription amount, more preferably approximately 1 / 2 of the prescription amount. Preferably, the solid dispersion is sieved through an 80-mesh sieve and the filler is sieved through a 40-mesh sieve before mixing. Preferably, the solid dispersion, disintegrant, gliding agent, and the remaining filler are added in equal increments.

[0176] Treatment methods and uses

[0177] One aspect of the present invention is to provide pharmaceutical compositions for treating, improving, or preventing melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis, said pharmaceutical compositions as defined above.

[0178] One aspect of the present invention is to provide a method for treating, improving, or preventing melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis, said method comprising administering an effective amount of a pharmaceutical composition as defined above to an individual in need.

[0179] One aspect of the present invention is to provide the use of the pharmaceutical composition as defined above in the preparation of a medicament for the treatment, improvement or prevention of melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis.

[0180] In one embodiment, the melanoma is an advanced melanoma, including but not limited to NRAS-mutant advanced melanoma and NF1-mutant advanced melanoma.

[0181] In one embodiment, the glioma is a low-grade glioma.

[0182] In one embodiment, the type I neurofibroma includes adult type I neurofibroma and pediatric type I neurofibroma.

[0183] In one embodiment, the type I neurofibroma is a plexiform neurofibroma associated with type I neurofibroma.

[0184] In one embodiment, the dendritic cell and histiocytic tumors include adult dendritic cell and histiocytic tumors and pediatric dendritic cell and histiocytic tumors.

[0185] In the methods or uses described in this invention, the pharmaceutical composition or drug may optionally be used in combination with a second therapeutic agent. The second therapeutic agent includes, but is not limited to, cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituximab, doxorubicin, gefitinib, or imatinib; cyclosporine, rapamycin, ascomycin, or their immunosuppressive analogues, such as cyclosporine A, cyclosporine G, FK-506, sirolimus, and everolimus; glucocorticoids, such as prednisone; cyclophosphamide; azathioprine; methotrexate; gold salts; sulfasalazine; antimalarial drugs; buquina; leflunomide; mizoribine; mycophenolic acid; phenolic esters; 15 - Deoxyguanidin, immunosuppressive monoclonal antibodies, such as monoclonal antibodies against leukocyte receptors, such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, ICD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatory compounds, such as CTLA41g; other drugs suitable for the treatment of melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis. Beneficial effects

[0186] Compound I is a MEK inhibitor with good clinical application prospects. Its crystal form A is stable, reproducible, and solvent-free, making it suitable for industrial production and long-term storage without the potential toxicity risks of residual solvents. However, the solubility of crystal form A is not pH-dependent and is poorly soluble in purified water and aqueous media within the physiological pH range, posing a great challenge to the development of oral solid dosage forms.

[0187] In the pharmaceutical composition of the present invention, compound I exists in an amorphous form, which significantly improves the solubility and dissolution rate of compound I, thereby improving the bioavailability of compound I. Through in-depth research on each component and its proportions, the present invention obtains a stable solid dispersion pharmaceutical composition. Even after long-term storage, compound I can still maintain a substantially amorphous form, avoiding the limited dissolution caused by the transformation of compound I from an amorphous form to a crystalline form.

[0188] This invention provides a solid dosage form suitable for oral administration through in-depth research on the components and dosages in pharmaceutical compositions. This solid dosage form is stable, has good bioavailability, has no food effect, and can produce the expected clinical efficacy with a lower unit dose, which helps to improve patient medication adherence.

[0189] Example

[0190] The present invention will now be described in further detail with reference to specific embodiments.

[0191] It should be noted that the following embodiments are merely examples to clearly illustrate the technical solutions of the present invention, and are not intended to limit the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here, and obvious variations or modifications derived therefrom are still within the protection scope of this invention. Unless otherwise specified, the instruments, equipment, and reagents used herein are commercially available.

[0192] The instruments, equipment, and testing conditions used in the following embodiments are shown below:

[0193] Nuclear magnetic resonance (NMR) spectroscopy: The NMR spectrum of compound I crystal form was detected using a Bruker AVANCE NEO 400MHz NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent.

[0194] X-ray powder diffraction (XRPD): The XRPD pattern of compound I crystal form was detected using a Bruker D8 Advance X-ray diffractometer. The instrument used Cu-Kα as the X-ray source and employed continuous PSD scanning mode, scanning the 2θ range from 3 to 42° with a step size of 0.02° and a scan time of 0.2 s. The phototube voltage and current for the tested sample were 40 kV and 40 mA, respectively.

[0195] Differential scanning calorimetry (DSC): The DSC spectrum of crystal form I of compound was detected using a TA Discovery DSC 25. The measurement temperature range was 30-300℃, the heating rate was 10℃ / min, the purge gas was nitrogen, and the purification gas flow rate was 60ml / min.

[0196] Thermogravimetric analysis (TGA): The TGA spectrum of compound I crystal form was detected using a TA Discovery 550 instrument. The measurement temperature range was room temperature (<30) to 350℃, and the heating rate was 10℃ / min.

[0197] High performance liquid chromatography (HPLC): Agilent Eclipse Plus C18; column: 4.6 mm × 100 mm, 3.5 μm; column temperature: 40 ℃; detection wavelength: 290 nm; mobile phase A: phosphate buffer; mobile phase B: acetonitrile; run time: 15 min.

[0198] Example 1: Preparation of crystal form A of compound I

[0199] Compound I was dissolved in solvent 1 to obtain 1 mL of a solution with a concentration of 20 mg / mL. Then, solvent 2 was added dropwise to this solution until a solid precipitated, or until the total volume of solvent 2 was increased to 7 times the total volume of solvent 1. The precipitated solid was filtered to obtain crystal form A. When solvent 1 is dimethyl sulfoxide (DMSO), solvent 2 is methanol, ethanol, or water; when solvent 1 is dimethylformamide (DMF), solvent 2 is methanol, ethanol, acetonitrile, or water.

[0200] Compound I was dissolved and clarified by heating with acetone and tetrahydrofuran, and then decolorized with activated carbon. The filtrate was condensed with acetone and crystallized. The resulting filter cake was further dissolved and clarified with DMSO. After dissolution, it was slowly added dropwise to a mixed solvent of purified water and ethanol at a controlled temperature of 65-70°C. The mixture was filtered, washed, and dried to obtain a white or off-white to pale yellow crystalline powder, i.e., crystal form A.

[0201] Compound I, DMSO, and activated carbon are added to a reaction vessel, heated to 30-50℃, stirred for 0.5-1 hour, cooled to 25-35℃, DMSO is added, and the mixture is filtered and washed. A mixed solvent of anhydrous ethanol and purified water is added, the temperature is raised to 65-70℃, stirred for 0.5-1 hour, cooled to 20-30℃, stirred for 1-2 hours, and a mixed solvent of anhydrous ethanol and purified water is added. The mixture is then filtered, washed, and dried to obtain a white or off-white to pale yellow crystalline powder, i.e., crystal form A.

[0202] 1 H-NMR (400MHz, DMSO-d6) δ10.93 (1H, d, J = 2.4), 9.95 (1H, s), 7.72 (1H, dd, J=10.4,2.0), 7.56-7.54(1H,m), 7.47(1H,t,J=7.6), 7.39(1H,m), 7.36-7 .33(1H,m), 7.25(1H,d,J=7.6), 7.01(1H,td,J=8.8,5.6), 4.02-3.96(1H, m), 2.95(3H,s), 2.71-2.65(1H,m), 1.08-1.03(4H,m), 0.96(4H,d,J=6.4).

[0203] The X-ray powder diffraction pattern of crystal form A is basically as shown in Figure 1.

[0204] As shown in Figure 2, the DSC curve of crystal form A shows an endothermic peak starting at approximately 278.72℃, with a peak temperature of approximately 280.12℃ and an enthalpy of approximately 97.123 J / g. This endothermic peak is due to the endothermic melting of the sample. As shown in Figure 3, crystal form A gradually loses 0.07% of its weight from room temperature to approximately 105.00℃, indicating that it does not contain water of crystallization or other crystallization solvents and is an anhydrous product. As shown in Figure 3, crystal form A has no obvious solvent residue.

[0205] Example 2: Preparation of crystal form B of compound I

[0206] Crystal form B was obtained in a crystallization system of ethyl acetate:petroleum ether = 1:4.

[0207] The X-ray powder diffraction pattern of crystal form B is basically as shown in Figure 4.

[0208] Example 3: Preparation of crystal form C of compound I

[0209] Crystal form C was obtained in a dimethyl sulfoxide / ethanol / water crystallization system.

[0210] The X-ray powder diffraction pattern of crystal form C is basically as shown in Figure 5.

[0211] Example 4: Preparation of crystal form D of compound I

[0212] Compound I was dissolved in DMF to obtain 1 mL of a solution with a concentration of 20 mg / mL. Then, 7 mL of methyl tert-butyl ether (MTBE) was added dropwise to the solution until a solid precipitated, or when the total volume of MTBE was increased to 7 times that of DMF. The precipitated solid was then filtered to obtain crystal form D.

[0213] Weigh approximately 20 mg of compound I into a 4 mL vial, add a certain amount of DMF to dissolve it, and filter. Take another 30 mL sample vial and add approximately 5 mL of ethyl formate or heptane to it. Place the 4 mL vial containing the clear liquid open over the 30 mL sample vial, seal the 30 mL sample vial, and let it stand at room temperature. A solid will precipitate, yielding crystal form D.

[0214] The X-ray powder diffraction pattern of crystal form D is basically as shown in Figure 6A.

[0215] As shown in Figure 7, the TGA spectrum of crystal form D shows a weight loss of 5.398% at 100-165℃, 3.636% at 165-200℃, and 0.681% at 250-300℃. The DSC spectrum shows two endothermic peaks at approximately 137.60℃ and 152.73℃, indicating the loss of DMF solvent. The third endothermic peak at approximately 279.68℃ is a melting peak. As shown in Figure 8, the NMR spectrum shows that crystal form D retains 9.36% DMF solvent. Crystal form D is a DMF solvate.

[0216] As shown in 6B of Figure 6, when the sample of crystal form D is heated to 200℃, crystal form D loses its solvent and transforms into crystal form A.

[0217] Example 5: Humidity-Induced Study

[0218] Two humidity-induced experiments were conducted: Group 1 at 60% humidity and Group 2 at 92.5% humidity. Approximately 10 mg of crystal form A sample was weighed into a 4 mL vial for each group. The vials were then placed open in a desiccator containing a saturated salt solution. After 7 days, the samples were removed for XRPD analysis. As shown in Figure 9, all obtained solids were crystal form A, and no crystal transformation occurred.

[0219] Example 6: Hygroscopicity Study

[0220] The experiment was conducted according to the guidelines for hygroscopicity testing of drugs in the Chinese Pharmacopoeia. The weight of the sample vial was recorded as m1; an appropriate amount of crystal form A sample was spread evenly at the bottom of the sample vial and weighed, recorded as m2; the sample vial was placed open under constant temperature and humidity conditions (25℃±1℃, 80% RH±2% RH) for 24 hours and then weighed, recorded as m3; the percentage increase in weight (%) was calculated using the following formula: Percentage increase in weight = (m3-m2) / (m2-m1)×100%

[0221] The hygroscopicity results for each batch are shown in Table 2. The weight gain due to hygroscopicity for each batch was less than 0.2%, indicating that crystal form A has no or almost no hygroscopicity.

[0222] Table 2 Results of hygroscopicity study

[0223] Example 7: Study on Crystal Form Stability

[0224] Crystal form A sample was subjected to high temperature (60℃), high humidity (90±5%RH, 25±2℃), and light irradiation (5000Lx, near-UV 84μW / cm). 2 The samples were placed under the following conditions for 30 days, under accelerated test conditions (40±2℃ / 75±5%RH) for 6 months, and under long-term test conditions for 24 months. The properties, related substances, moisture, and content showed no significant changes. The XRPD patterns of the samples under each test condition were consistent with the XRPD patterns of the reference standard, proving that crystal form A has good stability. See Figure 10-14 for details.

[0225] Table 3. Results of the stability study

[0226] Example 8: Solubility of crystal form A

[0227] The solubility of crystal form A in different media is shown in Table 4. It can be seen that the solubility of crystal form A is not pH dependent and is poorly soluble in purified water and aqueous media within the physiological pH range.

[0228] Table 4 Solubility of Compound I, Crystal Form A

[0229] FaSSIF represents simulated intestinal fluid in a fasting state; FeSSIF represents simulated intestinal fluid in a postprandial state; and SGF represents simulated gastric fluid.

[0230] Example 9: Study on the types of solid dispersion carriers

[0231] According to the formulation shown in Table 5, the crystal form A of compound I and the support are dissolved in a solvent to obtain a solution. This solution is spray-dried to obtain a powder, and then vacuum-dried to obtain a solid dispersion.

[0232] Table 5. Composition of solid dispersion formulations (unit: g)

[0233] *: Solvent is removed during the process.

[0234] Weigh an appropriate amount of solid dispersion or crystal form A of compound I, and add it to phosphate buffer solution at pH 6.8 to prepare a suspension of compound I with a concentration of 1 mg / mL. Then, magnetically stir at room temperature, take 1 mL samples at different time points, centrifuge, dilute the supernatant, inject the sample and perform HPLC analysis to measure the dynamic solubility of the solid dispersion. The results are shown in Table 6. The solid dispersions prepared with each carrier have a good solubilizing effect on compound I.

[0235] Table 6. Dynamic solubility results of various solid dispersions (unit: μg / mL)

[0236] The solid dispersion was analyzed by XRPD using the following parameters: a Bruker D8 Advance X-ray diffractometer was used with Cu-Kα as the X-ray source, continuous PSD rapid scanning mode was employed, the 2θ range was 8 to 10°, the step size was 0.02°, and the scanning time was 20 s. The phototube voltage and current for the test sample were 40 kV and 40 mA, respectively.

[0237] As shown in Figure 15, the solid dispersions prepared using PVP S630, PVP K29 / 32, HPMCP HP-55, and HPMCAS AS-LF as supports were all amorphous, characterized by the lack of sharp crystallographic X-ray peaks.

[0238] Example 10: Study on the ratio of drug to carrier in solid dispersions

[0239] According to the formulation in Table 7, a solid dispersion was prepared using crystal form A of compound I, and its dynamic solubility in phosphate buffer at pH 6.8 was tested as follows: an appropriate amount of solid dispersion was weighed and added to phosphate buffer at pH 6.8 to prepare a suspension with a concentration of 1 mg / mL of compound I. Then, the suspension was magnetically stirred at room temperature, and 1 mL samples were taken at different time points. After centrifugation, the supernatant was diluted, injected, and analyzed by HPLC. The results are shown in Table 8.

[0240] Table 7. Formulation composition of solid dispersions (unit: g)

[0241] Table 8. Dynamic solubility results of solid dispersions (unit: μg / mL)

[0242] As shown in the table above, the solubility of F2 is improved compared to F8. When the carrier ratio is further increased to 1:9, the solubility does not change significantly.

[0243] Example 11: Pharmacokinetic Study of Solid Dispersions

[0244] Pharmacokinetic studies were conducted on rats using a suspension of compound I crystal form A and a solid dispersion of compound I, F2, administered via gavage. The formulation of solid dispersion F2 was compound I:PVP K29 / 32 = 1:5, and the solvent was 0.5% CMC-Na + 1.0% SLS.

[0245] Table 9. Pharmacokinetic parameters of solid dispersions in rats.

[0246] As shown in Table 9, compared with the suspension of compound I crystal form A, the T of solid dispersion F2 is... max and C max Both were improved. Compound I, existing in an amorphous form in the solid dispersion, significantly improved its oral bioavailability and in vivo exposure.

[0247] Example 12: Effect of surfactants on the dissolution of solid dispersions

[0248] Solid dispersions were prepared using crystal form A of compound I according to the formulation in Table 10. The effect of the surfactant sodium dodecyl sulfate (SLS) on the dissolution rate of the solid dispersions was investigated using the following method: slurry method at 50 rpm, 500 mL medium, 37 °C, with each sample containing 1 mg of compound I. After sampling, the filtrate was diluted with ethanol at a 1:1 (v:v) ratio before injection.

[0249] Table 10. Formulation composition of solid dispersions (unit: g)

[0250] Table 11 Dissolution results of solid dispersions (%, n=3)

[0251] As shown in Table 11, compared with solid dispersions without SLS, solid dispersions containing SLS showed significantly improved dissolution rate and dissolution degree.

[0252] Example 13: Stability Study of Solid Dispersion

[0253] Solid dispersions were prepared using the F11 formulation, and their stability was investigated under accelerated conditions (40℃±2℃ / 75%RH±5%RH) and long-term conditions (25℃±2℃ / 60%RH±5%RH).

[0254] The crystal form detection method is the same as in Example 9. Content determination method: HPLC.

[0255] Table 12 Results of Accelerated Stability Tests for Solid Dispersions

[0256] Table 13 Results of Long-Term Stability Tests for Solid Dispersions

[0257] As shown in Tables 12 and 13, the solid dispersion of the present invention can maintain an amorphous state for up to 6 months under accelerated conditions and up to 12 months under long-term conditions. The content of compound I crystal form A is less than 2% after 24 months, and the quality is stable.

[0258] Example 14: Preparation of tablets

[0259] Example 14.1

[0260] Tablets were prepared using the direct powder compression method according to the formulation shown in the table below, and dissolution was determined. Dissolution test method: 0.05% SLS / pH 6.8 phosphate buffer was used as the dissolution medium, 500 ml, slurry method, 50 rpm.

[0261] Table 14. Formulation of 1mg tablets (mg / tablet)

[0262] Table 15 Dissolution rate of 1mg tablets (%, n=3)

[0263] The slow dissolution rate of F11-2 may be because the microcrystalline cellulose in the formulation is a water-insoluble filler that adsorbs the drug; F11-1 and F11-3 dissolve quickly and completely, indicating that using water-soluble fillers such as mannitol or anhydrous lactose for tableting can meet the dissolution requirements.

[0264] Example 14.2

[0265] Tablets were prepared using the direct powder compression method according to the formulation shown in the table below, and dissolution was determined. The dissolution determination method was the same as described above.

[0266] Example 14.1.

[0267] Table 16. Formulation of 0.1mg tablets (mg / tablet)

[0268] Table 17 Dissolution rate (%, n=3) of 0.1mg tablets

[0269] As shown in Table 17, changes in lubricant content do not affect tablet dissolution.

[0270] Example 14.3

[0271] (1) F11-5 tablets were coated with water-soluble film coating material (Opadry 03B28796-CN white) to obtain F11-6 tablets. The dissolution of F11-5 tablets and F11-6 tablets was determined. The dissolution determination method was the same as in Example 14.1. The results are shown in Table 18.

[0272] Table 18 Dissolution rate of tablets before and after coating (%, n=3)

[0273] The results showed that the dissolution rate of the coated tablets prepared with water-soluble film coating material was not significantly different from that of the tablet core, indicating that the coating material had no effect on the dissolution of Compound I tablets.

[0274] (2) Using the formulation shown in Table 19, tablet cores with a specification of 4 mg were prepared by direct powder compression. These cores were then coated with a water-soluble film coating material (Opadry 03B28796-CN, white). The effect of different coating weight gain on tablet dissolution was investigated. The dissolution rate was determined using a pH 6.8 buffer medium containing 0.1% SLS, 500 ml, slurry method, 50 rpm. The results are shown in Table 20. The dissolution curves of products with different coating weight gain all reached 90% at 30 min.

[0275] Table 19. Composition of the 4mg tablet core formulation

[0276] Table 20 Dissolution curves of 4mg tablets with different coating weight gain in pH 6.8 (0.1% SLS) medium.

[0277] Example 14.4

[0278] Tablets were prepared according to the formulation shown in Table 21, and their stability and dissolution profiles were determined. The tablet preparation included the following steps: (1) Compound I was pre-prepared into a solid dispersion with polyvinylpyrrolidone and sodium dodecyl sulfate by spray drying; (2) the remaining excipients were added, mixed, and then tableted and coated with film.

[0279] Table 21 Prescriptions for 1mg and 4mg tablets (mg / tablet)

[0280] Dissolution curves for 1 mg and 4 mg tablets were determined using the Chinese Pharmacopoeia Apparatus II (paddle method) at 50 rpm, with phosphate buffer containing 0.1% SLS and pH 6.8 as the dissolution medium (900 ml) and a medium temperature of 37.0 ± 0.5 °C.

[0281] Table 22 Dissolution profiles of 1 mg tablets in 0.1% SLS at pH 6.8 (n = 12)

[0282] Table 23 Dissolution profiles of 4mg tablets in 0.1% SLS at pH 6.8 (n=12)

[0283] As shown in Tables 22 and 23, both sizes of tablets dissolved more than 90% within 15 minutes.

[0284] Stability tests were conducted on 1 mg and 4 mg tablets packaged in HDPE bottles. Accelerated test conditions were 40℃±2℃ / 75%RH±5%RH, and long-term test conditions were 25℃±2℃ / 60%RH±5%RH.

[0285] Table 24 Accelerated Test Results for 1 mg and 4 mg Tablets

[0286] The dissolution test results in the table above are average values ​​(n=5).

[0287] Table 25 Results of long-term trials of 1mg tablets

[0288] Table 26 Results of long-term trials of 4mg tablets

[0289] *Crystal form detection method: A Bruker D8 Advance X-ray diffractometer or equivalent equipment was used with Cu-Kα as the X-ray source. A continuous PSD rapid scanning mode was employed, scanning the 2θ range from 8 to 10° with a step size of 0.02° and a scanning time of 5 seconds. The phototube voltage and current for the tested sample were 40 kV and 40 mA, respectively.

[0290] Dissolution test method: Paddle method / 50 rpm / pH 6.8 + 0.05% SLS / 500ml

[0291] As shown in Tables 24-26, there were no significant changes in any of the test items for the two specifications of tablets compared to the initial values ​​after 6 months of accelerated testing and 24 months of long-term testing.

[0292] Example 15: Study on tablet preparation process

[0293] Using the formulation in Table 19, 1 mg and 4 mg tablets were prepared by direct powder compression. The effects of the mixing process parameters shown in Table 27 on the content and mixing uniformity were investigated. The mixing process included sieving the solid dispersion, sieving the excipient mannitol, the order of mannitol addition, and the mixing method involving the addition of silica and croscarmellose sodium for further mixing. Finally, magnesium stearate was added and the mixture was fully mixed.

[0294] Table 27 Mixing Process Parameters

[0295] Table 28. Content determination results for each group (n=10)

[0296] As shown in Table 28, the method of premixing a portion of the filler before adding the solid dispersion and other excipients (excluding lubricant) results in a total mixed content closer to the theoretical content compared to other mixing methods. After the solid dispersion passed through an 80-mesh sieve, premixing was performed using an equal-incremental mixing method, followed by passing the mixture through a 40-mesh sieve three times and then through a 0.8mm sieve three times using a granulator. The mixing uniformity met the required limits in all cases.

[0297] Example 16: Human Pharmacokinetic Study

[0298] The pharmacokinetic characteristics of the pharmaceutical composition of the present invention and the effect of food on pharmacokinetics were evaluated in healthy male subjects. Healthy adults were given a single oral dose of 8 mg of the tablets of the present invention (4 mg tablets as shown in Table 19) after an empty stomach or a high-fat / low-fat diet, as shown in Tables 29 and 30. Through in-depth studies of each component and its dosage, the tablets of the present invention demonstrated good oral bioavailability in humans. The effects of high-fat and low-fat diets on the pharmacokinetics of the tablets of the present invention were not clinically significant. The tablets of the present invention have no food effect and can be taken on an empty stomach or after a meal.

[0299] Table 29 Pharmacokinetics of the tablets of this invention

[0300] Unless otherwise stated, the data are geometric mean (geometric coefficient of variation).

[0301] a The data is the median.

[0302] Table 30 Food Effects of the Tablets of the Present Invention

[0303] The above description is merely a specific embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent transformations made using the present invention, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

A pharmaceutical composition comprising a) N-[3-[6-cyclopropyl-3-fluoro-4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl]phenyl]cyclopropanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof; b) at least one carrier; wherein compound I or a pharmaceutically acceptable salt thereof is distributed substantially in an amorphous form in the carrier. The pharmaceutical composition according to claim 1, characterized in that: The carrier is selected from one or a combination of copovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, or other substances that are hydrophilic or water-soluble at pH in the gastrointestinal tract. The pharmaceutical composition according to claim 1 or 2 is characterized in that: The weight ratio of compound I or a pharmaceutically acceptable salt thereof to the carrier in the pharmaceutical composition is in the range of about 1:1 to about 1:

10. The pharmaceutical composition according to any one of claims 1-3 is characterized in that: The pharmaceutical composition also contains c) at least one surfactant. The pharmaceutical composition according to claim 4 is characterized in that: The surfactant is selected from one or a combination of sodium dodecyl sulfate, polysorbate 80, vitamin E-TPGS, or other substances that can improve the dissolution of compound I or its pharmaceutically acceptable salt. The pharmaceutical composition according to claim 4 or 5 is characterized in that: The weight ratio of compound I or a pharmaceutically acceptable salt thereof, carrier, and surfactant in the pharmaceutical composition is in the range of about 1:1:0.5 to about 1:10:

2. The pharmaceutical composition according to any one of claims 1-6 is characterized in that: The total weight of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition shall be no more than about 5% in crystalline form. The pharmaceutical composition according to claim 7 is characterized in that: The crystalline form of compound I has a characteristic diffraction peak at the following 2θ angle: 8.89±0.2°. The pharmaceutical composition according to claim 8, characterized in that: The crystalline form of compound I has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, and 24.86±0.2°. The pharmaceutical composition according to any one of claims 1-9 is characterized in that: The pharmaceutical composition is a solid dispersion. The pharmaceutical composition according to claim 10 is characterized in that, The solid dispersion was prepared by spray drying. The pharmaceutical composition according to any one of claims 1-6 is characterized in that, The pharmaceutical composition further comprises d) at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 12 is characterized in that: The pharmaceutical composition is selected from tablets, capsules, granules or other oral solid dosage forms that can meet bioequivalence requirements. The pharmaceutical composition according to claim 13 is characterized in that: The pharmaceutical composition is a tablet; the content of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the range of about 0.05% to about 3% (w / w); the pharmaceutically acceptable excipients include fillers, flow aids, lubricants, and disintegrants; the content of fillers in the pharmaceutical composition is in the range of about 50% to about 90% (w / w), the content of flow aids is in the range of about 0.5% to about 10% (w / w), the content of lubricants is in the range of about 0.2% to about 5.0% (w / w), and the content of disintegrants is in the range of about 1% to about 15% (w / w). The pharmaceutical composition according to claim 14 is characterized in that: The filler is selected from one or a combination of lactose, mannitol, and sorbitol; the flow aid is selected from one or a combination of talc and colloidal silica; the lubricant is selected from one or a combination of magnesium stearate, calcium stearate, sodium stearate, and sodium stearate fumarate; and the disintegrant is selected from one or a combination of sodium carboxymethyl starch, croscarmellose sodium, and calcium carboxymethyl cellulose. The pharmaceutical composition according to any one of claims 12-15 is characterized in that: The crystalline form of compound I or a pharmaceutically acceptable salt thereof constitutes no more than about 5% of the total weight of compound I or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 16 is characterized in that: The crystalline form of compound I has a characteristic diffraction peak at the following 2θ angle: 8.89±0.2°. The pharmaceutical composition according to claim 17 is characterized in that: The crystalline form of compound I has characteristic diffraction peaks at the following 2θ angles: 8.89±0.2°, 16.50±0.2°, 18.25±0.2°, 24.25±0.2°, and 24.86±0.2°. A pharmaceutical composition for the treatment, improvement or prevention of melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis, said pharmaceutical composition as defined in any one of claims 1-18. A method for treating, improving, or preventing melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis, said method comprising administering to an individual in need an effective amount of the pharmaceutical composition as described in any one of claims 1-18. Use of the pharmaceutical composition according to any one of claims 1-18 in the preparation of a medicament, characterized in that: The drug is used to treat, improve, or prevent melanoma, glioma, neurofibroma type I, arteriovenous malformation, dendritic cell and histiocytic tumors, and Langerhans cell histiocytosis.

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